The present invention relates to novel substituted guanidine derivatives, prodrugs thereof or pharmaceutically acceptable salts of the derivatives or prodrugs, and a process for production of the derivatives, prodrugs or salts. The compounds of the present invention inhibit the sodium/proton (Na+/H+) exchange transport system and hence are useful as a therapeutic or prophylactic agent for diseases caused by the acceleration of the sodium/proton (Na+/H+) exchange transport system, for example, hypertension, arrhythmia, angina pectoris, cardiac hypertrophy, diabetes mellitus, organ disorders associated with ischemia or ischemic reperfusion [e.g. cardiac ischemic reperfusion-injury, acute renal failure, or disorders induced by surgical treatment such as organ transplantation or percutaneous transluminal coronary angioplasty (PTCA)], cerebro-ischemic injury [e.g. injury associated with cerebral infarction, injury caused as sequelae of stroke, or brain edema], diseases caused by hyperplasia such as hyperplasia of fibroblast, hyperplasia of smooth muscle cells or hyperplasia of mesangium cells, which diseases are, for example, atherosclerosis, pulmonary fibrosis, hepatic fibrosis, renal fibrosis, glomerular nephrosclerosis, organ hypertrophy, prostatic hypertrophy, diabetic complications or restenosis after PTCA, or diseases caused by endotherial cell injury.
As substituted guanidine derivatives having inhibitory effect on the sodium/proton (Na+/H+) exchange transport system, there are known, for example, pyrazinoylguanidine derivatives represented by amiloride (for instance, J. Membrane Biol., Vol. 105, 1(1988); Circulation, Vol. 79, 1257(1989)). It has been reported that benzoylguanidine derivatives inhibit the sodium/proton (Na+/H+) exchange transport system and hence have antiarrhythmic effect (for instance, J. Mol. Cell. Cardiol., Vol. 24, Suppl. I, S.92(1992); J. Mol. Cell. Cardiol., Vol. 24, Suppl. I, S.117(1992); Japanese Patent Unexamined Publication Nos. 5-339228, 6-9545, 6-345715 and 7-109251). It has also been reported that polycyclic aroylguanidine derivatives inhibit the sodium/proton (Na+/H+) exchange transport system (for instance, Japanese Patent Unexamined Publication Nos. 7-10839, 7-145149, 7-206823, 8-41028, 8-225513, 8-277269, 9-77753 and 9-291076). In addition, it has been reported that indenoylguanidine derivatives inhibit the sodium/proton (Na+/H+) exchange transport system (for instance, Japanese Patent Unexamined Publication Nos. 8-291131 and 9-268172). Furthermore, it has been reported that acryloylguanidine derivatives inhibit the sodium/proton (Na+/H+) exchange transport system (for instance, Japanese Patent Unexamined Publication Nos. 8-319266, 9-52823, 9-59245, 9-67332, 9-67340 and 9-249660).
The present invention is intended to provide novel substituted guanidine derivatives, prodrugs thereof or pharmaceutically acceptable salts of the derivatives or prodrugs, which inhibit the sodium/proton (Na+/H+) exchange transport system and hence are useful as a therapeutic or prophylactic agent for diseases caused by the acceleration of the sodium/proton (Na+/H+) exchange transport system, for example, hypertension, arrhythmia, angina pectoris, cardiac hypertrophy, diabetes mellitus, organ disorders associated with ischemia or ischemic reperfusion [e.g. heart muscle ischemic reperfusion-associated disorders, acute renal failure, or disorders induced by surgical treatment such as organ transplantation or percutaneous transluminal coronary angioplasty (PTCA)], cerebro-ischemic disorders [e.g. disorders associated with cerebral infarction, disorders caused after cerebral apoplexy as sequelae, or cerebral edema], diseases caused by excessive cell proliferation such as proliferation of fibroblast, proliferation of smooth muscle cells or proliferation of mesangium cells, which diseases are, for example, atherosclerosis, pulmonary fibrosis, hepatic fibrosis, renal fibrosis, glomerular nephrosclerosis, organ hypertrophy, prostatic hypertrophy, diabetic complications or recurrent stricture after PTCA, or diseases caused by endotherial cell injury; and
a process for production of said derivatives, prodrugs thereof, or salts of the derivatives or prodrugs.
The present invention includes the aspects described in the following items [1] to [23].
[1]
A compound represented by the general formula (1): 
wherein R1 is a hydrogen atom, an alkyl group, a substituted alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, a cycloalkenyl group, a saturated heterocyclic group, an aromatic group, an acyl group, a halogen atom, xe2x80x94OR6, xe2x80x94S(O)nR7, xe2x80x94Qxe2x80x94Ra or 
wherein A is an oxygen atom or xe2x80x94S(O)nxe2x80x94, R10 is a hydrogen atom, an alkyl group, a substituted alkyl group, an acyl group, xe2x80x94S(O)nR7 or xe2x80x94Qxe2x80x94Ra, and the ring is a 3- to 8-membered saturated heterocyclic group composed of a nitrogen atom and carbon atoms;
R2, R3, R4 and R5 are independently a hydrogen atom, an alkyl group, a substituted alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, a cycloalkenyl group, a saturated heterocyclic group, an aromatic group, an acyl group, a carboxyl group, an alkoxycarbonyl group, a halogen atom, a nitro group, xe2x80x94OR6, xe2x80x94N(R8)R9, xe2x80x94CON(R8)R9, xe2x80x94SO2N(R8)R9, xe2x80x94S(O)nR7, xe2x80x94Qxe2x80x94Ra or 
xe2x80x83wherein Axe2x80x2 is an oxygen atom, xe2x80x94S(O)nxe2x80x94 or xe2x80x94N(R51)xe2x80x94, and R10 and the ring are as defined above;
Y1, Y2, Y3 and Y4, which may be the same or different, are independently a single bond, xe2x80x94CH2xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94COxe2x80x94, xe2x80x94C(xe2x95x90C(R12)R13)xe2x80x94 or xe2x80x94N(R11)xe2x80x94, provided that at least two of Y1 through Y4 are independently a group other than a single bond;
Z may be absent, or one or more Zs may be present and are, the same or different, independently the following substituent for a hydrogen atom bonded to any of the carbon atoms constituting the ring formed by Y1 through Y4: an alkyl group, a substituted alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, a cycloalkenyl group, a saturated heterocyclic group, a halogen atom, a carboxyl group, an alkoxycarbonyl group, an aromatic group, an acyl group, xe2x80x94OR6, xe2x80x94N(R8)R9, xe2x80x94S(O)nR7, xe2x80x94C(O)N(R8)R9, xe2x80x94SO2N(R8)R9, or xe2x80x94Qxe2x80x94Ra;
Q is a substituted or unsubstituted lower alkylene group;
Ra is a substituted or unsubstituted vinyl group, or a substituted or unsubstituted ethynyl group;
R6 is a hydrogen atom, an alkyl group, a substituted alkyl group, a cycloalkyl group, a cycloalkenyl group, a saturated heterocyclic group or an aromatic group;
R7 is an alkyl group, a substituted alkyl group or an aromatic group;
n is an integer of 0, 1 or 2;
R8 and R9 are independently a hydrogen atom, an alkyl group, a substituted alkyl group, a cycloalkyl group, a cycloalkenyl group, a saturated heterocyclic group, an aromatic group, an acyl group, xe2x80x94S(O)2R7 or xe2x80x94Qxe2x80x94Ra, or R8 and R9, when taken together with the nitrogen atom to which they are bonded, form a 5- to 7-membered saturated cyclic amino group which may contain other heteroatom(s) in the ring and may be substituted by one or more alkyl groups, substituted alkyl groups, hydroxyl groups or xe2x80x94OR6 groups;
R11 is a hydrogen atom, an alkyl group, a substituted alkyl group, a cycloalkyl group, a saturated heterocyclic group, an aromatic group, an acyl group, xe2x80x94S(O)2R7 or xe2x80x94Qxe2x80x94Ra;
R51 is a hydrogen atom, an alkyl group, a substituted alkyl group, a cycloalkyl group, a saturated heterocyclic group, an aromatic group, an acyl group, xe2x80x94S(O)2R7 or xe2x80x94Qxe2x80x94Ra; and
R12 and R13 are independently a hydrogen atom, an alkyl group, a substituted alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, a cycloalkenyl group, a saturated heterocyclic group, a halogen atom, a carboxyl group, an alkoxycarbonyl group, an aromatic group, an acyl group, xe2x80x94OR6, xe2x80x94CON(R8)R9, xe2x80x94S(O)nR7 or xe2x80x94Qxe2x80x94Ra, a prodrug of said compound, or a pharmaceutically acceptable salt of said compound or prodrug.
[2]
A compound, a prodrug thereof or a pharmaceutically acceptable salt of the compound or prodrug according to [1], wherein Y1, Y2, Y3 and Y4, which may be the same or different, are independently a single bond, xe2x80x94CH2xe2x80x94, xe2x80x94COxe2x80x94, xe2x80x94C(xe2x95x90C(R12)R13)xe2x80x94 or xe2x80x94N(R11)xe2x80x94.
[3]
A compound, a prodrug thereof or a pharmaceutically acceptable salt of the compound or prodrug according to [1], wherein one or two of Y1 through Y4 is a single bond, and the others are independently a group other than a single bond.
[4]
A compound, a prodrug thereof or a pharmaceutically acceptable salt of the compound or prodrug according to [2], wherein one or two of Y1 through Y4 is a single bond, and the others are independently a group other than a single bond.
[5]
A compound, a prodrug thereof or a pharmaceutically acceptable salt of the compound or prodrug according to [1], wherein one of Y1 through Y4 is a single bond, and the others are independently a group other than a single bond.
[6]
A compound, a prodrug thereof or a pharmaceutically acceptable salt of the compound or prodrug according to [2], wherein one of Y1 through Y4 is a single bond, and the others are independently a group other than a single bond.
[7]
A compound, a prodrug thereof or a pharmaceutically acceptable salt of the compound or prodrug according to [5], wherein Z is an alkyl group or a substituted alkyl group.
[8]
A compound, a prodrug thereof or a pharmaceutically acceptable salt of the compound or prodrug according to [5] or [7], wherein each of Y1, Y2 and Y3 is xe2x80x94CH2xe2x80x94 which may be substituted by one Z or two or more Zs which may be the same or different, and Y4 is a single bond.
[9]
A compound, a prodrug thereof or a pharmaceutically acceptable salt of the compound or prodrug according to [8], wherein one of Y1, Y2 and Y3 is xe2x80x94CH2xe2x80x94 substituted by one Z or two Zs which may be the same or different, and the two others are independently unsubstituted xe2x80x94CH2xe2x80x94, and Y4 is a single bond.
[10]
A compound, a prodrug thereof or a pharmaceutically acceptable salt of the compound or prodrug according to [8], wherein Y1 is xe2x80x94CH2xe2x80x94 substituted by one Z or two Zs which may be the same or different, Y2 and Y3 are independently unsubstituted xe2x80x94CH2xe2x80x94, and Y4 is a single bond.
[11]
A compound, a prodrug thereof or a pharmaceutically acceptable salt of the compound or prodrug according to [8], wherein Y3 is xe2x80x94CH2xe2x80x94 substituted by one Z or two Zs which may be the same or different, Y1 and Y2 are independently unsubstituted xe2x80x94CH2xe2x80x94, and Y4 is a single bond.
[12]
A compound, a prodrug thereof or a pharmaceutically acceptable salt of the compound or prodrug according to any one of [1] to [11], wherein one of R2, R3, R4 and R5 is a substituted alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, a cycloalkenyl group, an acyl group, a carboxyl group, an alkoxycarbonyl group, xe2x80x94CON(R8)R9, xe2x80x94SO2N(R8)R9, xe2x80x94S(O)nR7, xe2x80x94Qxe2x80x94Ra or 
[13]
A compound, a prodrug thereof or a pharmaceutically acceptable salt of the compound or prodrug according to any one of [1] to [12], wherein at least one Z is present.
[14]
A compound, a prodrug thereof or a pharmaceutically acceptable salt of the compound or prodrug according to any one of [1] to [12], wherein at least one of Y1 through Y4 is xe2x80x94N(R11)xe2x80x94 in which R11 is an alkyl group, a substituted alkyl group, a cycloalkyl group, a saturated heterocyclic group, an aromatic group, an acyl group, xe2x80x94S(O)2R7 or xe2x80x94Qxe2x80x94Ra.
[15]
N-(aminoiminomethyl)-7-methyl-6,7-dihydro-5H-benzocycloheptene-8-carboxamide or
N-(aminoiminomethyl)-7,7-dimethyl-6,7-dihydro-5H-benzocycloheptene-8-carboxamide, a prodrug thereof, or a pharmaceutically acceptable salt of any one of these compounds or prodrugs.
[16]
A process for producing a compound of the formula (1), a prodrug thereof or a pharmaceutically acceptable salt of the compound or prodrug according to [1], which comprises reacting a compound represented by the formula (2): 
wherein R1, R2, R3, R4, R5, Y1, Y2, Y3, Y4 and Z are as defined in [1], and J is a hydroxyl group or a leaving group replaceable by a nucleophilic reagent, with guanidine.
[17]
A pharmaceutical composition comprising a compound, a prodrug thereof or a pharmaceutically acceptable salt of the compound or prodrug according to any one of [1] to [15].
[18]
A sodium/proton exchange transport system inhibitor comprising a compound, a prodrug thereof or a pharmaceutically acceptable salt of the compound or prodrug according to any one of [1] to [15].
[19]
A pharmaceutical composition for the treatment or prophylaxis of hypertension, arrhythmia, angina pectoris, cardiac hypertrophy, diabetes mellitus, organ disorders associated with ischemia or ischemic reperfusion, cerebro-ischemic disorders, diseases caused by excessive cell proliferation, or diseases caused by endothelial cell injury, which comprises a compound, a prodrug thereof or a pharmaceutically acceptable salt of the compound or prodrug according to any one of [1] to [15].
[20]
Use of a compound, a prodrug thereof or a pharmaceutically acceptable salt of the compound or prodrug according to any one of [1] to [15] in the manufacture of a sodium/proton exchange transport system inhibitor.
[21]
Use of a compound, a prodrug thereof or a pharmaceutically acceptable salt of the compound or prodrug according to any one of [1] to [15] in the manufacture of a pharmaceutical composition for the treatment or prophylaxis of hypertension, arrhythmia, angina pectoris, cardiac hypertrophy, diabetes mellitus, organ disorders associated with ischemia or ischemic reperfusion, cerebro-ischemic disorders, diseases caused by excessive cell proliferation, or diseases caused by endothelial cell injury.
[22]
A method for inhibiting a sodium/proton exchange transport system which comprises administering a compound, a prodrug thereof or a pharmaceutically acceptable salt of the compound or prodrug according to any one of [1] to [15] to a mammal including a human being, in a pharmacologically effective amount.
[23]
A method for treating or preventing hypertension, arrhythmia, angina pectoris, cardiac hypertrophy, diabetes mellitus, organ disorders associated with ischemia or ischemic reperfusion, cerebro-ischemic disorders, diseases caused by excessive cell proliferation, or diseases caused by endothelial cell injury, which comprises administering a compound, a prodrug thereof or a pharmaceutically acceptable salt of the compound or prodrug according to any one of [1] to [15] to a mammal including a human being, in a pharmacologically effective amount.
The various groups in the present invention are explained below.
As the alkyl group, there may be exemplified linear or branched alkyl groups of 8 or less carbon atoms, such as methyl, ethyl, propyl, 2-propyl, butyl, 2-butyl, 2-methylpropyl, 1,1-dimethylethyl, pentyl, hexyl, heptyl, octyl, etc.
The cycloalkyl group may be either an unsubstituted one or a substituted one having as the substituent(s) 1 to 4 alkyl groups, substituted alkyl groups, hydroxyl groups or xe2x80x94OR6 groups, and includes, for example, 3- to 8-membered cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, 2-methylcyclopentyl, 3-methylcyclopentyl, 2-methylcyclohexyl, 3-methylcyclohexyl, 4-methylcyclohexyl, 2-hydroxycyclopentyl, 3-hydroxycyclopentyl, 2-hydroxycyclohexyl, 3-hydroxycyclohexyl, 4-hydroxycyclohexyl, 2-(hydroxymethyl)cyclopentyl, 3-(hydroxymethyl)cyclopentyl, 2-(hydroxymethyl)cyclohexyl, 3-(hydroxymethyl)cyclohexyl, 4-(hydroxymethyl)cyclohexyl, 2-(aminomethyl)cyclopentyl, 3-(aminomethyl)cyclopentyl, 2-(aminomethyl)cyclohexyl, 3-(aminomethyl)cyclohexyl, 4-(aminomethyl)cyclohexyl, 2-(methoxymethyl)-cyclopentyl, 3-(methoxymethyl)cyclopentyl, 2-(methoxymethyl)cyclohexyl, 3-(methoxymethyl)cyclohexyl, 4-(methoxymethyl)cyclohexyl, etc.
The cycloalkenyl group may be either an unsubstituted one or a substituted one having as the substituent(s) 1 to 4 alkyl groups, substituted alkyl groups, hydroxyl groups or xe2x80x94OR6 groups, and includes, for example, 3- to 8-membered cycloalkenyl groups having a double bond, such as 1-cyclopentenyl, 2-cyclopentenyl, 3-cyclopentenyl, 1-cyclohexenyl, 2-cyclohexenyl, 3-cyclohexenyl, etc.
The saturated heterocyclic group may be either an unsubstituted one or a substituted one having as the substituent(s) 1 to 4 alkyl groups, substituted alkyl groups, hydroxyl groups or xe2x80x94OR6 groups, and includes, for example, 3- to 8-membered saturated heterocyclic groups having an oxygen atom or a sulfur atom, such as 2-tetrahydrofuranyl, 3-tetrahydrofuranyl, 2-tetrahydro-2H-pyranyl, 4-tetrahydro-4H-pyranyl, etc.
The halogen atom includes, for example, iodine, fluorine, chlorine and bromine atoms.
As the alkoxycarbonyl group, there may be exemplified linear or branched alkoxycarbonyl groups of 6 or less carbon atoms, such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, 2-propoxycarbonyl, etc.
The aromatic group includes substituted or unsubstituted aryl groups and substituted or unsubstituted heteroaryl groups. As the aryl groups, there may be exemplified aryl groups of 10 or less carbon atoms, such as phenyl, naphthyl, etc. As the heteroaryl groups, there may be exemplified 5- or 6-membered heteroaryl groups containing 1 to 4 nitrogen atoms and 5- or 6-membered heteroaryl groups containing 0 to 2 nitrogen atoms and an oxygen atom or a sulfur atom, for example, 2-, 3- or 4-pyridyl, pyrrolyl, isoimidazolyl, triazolyl, tetrazolyl, 2- or 3-furyl, 2- or 3-thienyl, 1-, 3- or 4-oxazolyl, and 3-, 4- or 5-isoxazolyl.
The substituent of each of the substituted aryl group and the substituted heteroaryl group includes alkyl groups, substituted alkyl groups, halogen atoms, nitro group, alkoxycarbonyl groups, carboxyl group, and groups represented by the formula xe2x80x94OR6, xe2x80x94N(R8)R9, xe2x80x94CON(R8)R9, xe2x80x94SO2N(R8)R9 or xe2x80x94S(O)nR7.
When R1, R2, R3, R4 or R5 is a group represented by the formula xe2x80x94OR6 wherein R6 is an aromatic group, typical examples of the xe2x80x94OR6group are phenoxy group and substituted phenoxy groups. Examples of the substituted phenoxy groups are phenoxy groups substituted by, for example, a nitro group; a xe2x80x94N(R8)R9 group wherein each of R8 and R9 is, for example, a hydrogen atom or an alkyl group; or a substituted alkyl group (the substituent is, for example, a hydroxyl group or a xe2x80x94N(R8)R9 group). More specific examples of the substituted phenoxy groups are o-, m- or p-nitrophenoxy, o-, m- or p-aminophenoxy, o-, m- or p-(dimethylamino)phenoxy, o-, m- or p-(aminomethyl)phenoxy, o-, m- or p-(dimethylaminomethyl)phenoxy, etc.
As the alkoxy group, there may be exemplified linear or branched alkoxy groups of 6 or less carbon atoms, such as methoxy, ethoxy, isopropoxy, tert-butoxy, etc.
As the heteroatom(s) of the 5- to 7-membered saturated cyclic amino group which R8 and R9 form when taken together with the nitrogen atom to which they are bonded, and which may contain other heteroatom(s) in the ring, there may be exemplified oxygen atom, nitrogen atom and sulfur atom. Specific examples of the 5- to 7-membered cyclic amino group are 5- to 7-membered ring groups containing 1 to 3 nitrogen atoms and 5- to 7-membered ring groups containing a nitrogen atom and an oxygen atom. More specific examples of the 5- to 7-membered cyclic amino group are 1-pyrrolidinyl, 1-piperidino, 1-piperazinyl, morpholino, 1-(4-methyl)piperazinyl, etc.
The substituent of the substituted alkyl group includes halogen atoms, hydroxyl group, alkoxy groups, cycloalkyl groups, cyano group, carboxyl group, alkoxycarbonyl groups, acyl groups, aromatic groups, and groups represented by the formula xe2x80x94CONRpRq wherein Rp and Rq is independently a hydrogen atom or an alkyl group, or Rp and Rq, when taken together, represent a 5- to 7-membered saturated cyclic amino group which may contain another heteroatom; xe2x80x94N(R8)R9; or 
wherein Rxe2x80x3 is a hydrogen atom, an alkyl group or a substituted alkyl group, and the ring is a 3- to 8-membered saturated heterocyclic group composed of a nitrogen atom and carbon atoms. Particularly when R1, R2, R3, R4, R5, R7, R12, R13 or Z is a substituted alkyl group, the substituent includes, for example, cycloalkyl groups, halogen atoms, hydroxyl group, alkoxy groups, carboxyl group, alkoxycarbonyl groups, acyl groups, aromatic groups and groups represented by the formula xe2x80x94CONRpRq or xe2x80x94N(R8)R9. When R8, R9, R10 or R11 is a substituted alkyl group, the substituent includes, for example, cycloalkyl groups, hydroxyl group, alkoxy groups, carboxyl group, alkoxycarbonyl groups, acyl groups, aryl groups, and groups represented by the formula xe2x80x94CONRpRq or xe2x80x94N(R8)R9. As the alkyl portion of the substituted alkyl group, there may be exemplified the same groups as those exemplified above as the alkyl group.
Such a substituted alkyl group includes, for example, alkyl groups of 1 to 5 carbon atoms substituted by a cycloalkyl group of 3 to 6 carbon atoms; polyhaloalkyl groups of 1 to 5 carbon atoms; hydroxyalkyl groups of 1 to 6 carbon atoms, alkoxyalkyl groups of 2 to 6 carbon atoms; cyanoalkyl groups of 2 to 6 carbon atoms; carboxyalkyl groups of 2 to 6 carbon atoms; alkoxycarbonylalkyl groups of 3 to 8 carbon atoms; alkanoylalkyl groups of 3 to 8 carbon atoms; aroylalkyl groups of 16 or less carbon atoms; substituted or unsubstituted phenyl- or naphthyl-C1xcx9cC5 alkyl groups; carbamoyl-C1xcx9cC3 alkyl groups which may have one or two C1xcx9cC3 alkyl groups as a substituent(s) on the nitrogen atom; amino-C1xcx9cC5 alkyl groups which may have one or two C1xcx9cC3 alkyl or C7xcx9cC11 aralkyl groups as a substituent(s) on the nitrogen atom; and 5- to 7-membered saturated cyclic amino-C1xcx9cC3 alkyl groups.
As the aralkyl group, alkyl groups substituted by an aryl group may be exemplified.
Typical examples of the substituted alkyl group are polyhaloalkyl groups of 1 to 3 carbon atoms, such as trifluoromethyl, trifluoroethyl, trichloromethyl, etc.; hydroxyalkyl groups of 1 to 6 carbon atoms, such as hydroxymethyl, hydroxyethyl, 1-hydroxyethyl, etc.; aminoalkyl groups of 1 to 5 carbon atoms, such as aminomethyl, aminoethyl, 1-aminoethyl, etc.; alkoxyalkyl groups of 1 to 6 carbon atoms, such as methoxyethyl, ethoxyethyl, methoxypropyl, etc.; carboxyalkyl groups of 2 to 6 carbon atoms, such as carboxyethyl, carboxypropyl, etc.; alkoxycarbonylalkyl groups of 3 to 7 carbon atoms, such as methoxycarbonylmethyl, ethoxycarbonylmethyl, methoxycarbonylethyl, etc.; phenyl- or naphthyl-C1xcx9cC5 alkyl groups (which may have in the phenyl or naphthyl portion a substituent such as a C1xcx9cC3 alkyl group, halogen atom, nitro group, amino group, hydroxyl group, C1xcx9cC3 alkoxy group or the like) such as benzyl, phenylethyl, phenylpropyl, phenylbutyl, 1- or 2-naphthylmethyl, etc.; carbamoyl-C1xcx9cC3 alkyl groups which may have one or two C1xcx9cC3 alkyl groups as a substituent(s) on the nitrogen atom, for example, carbamoylmethyl, carbamoylethyl, dimethylcarbamoylmethyl, etc.; amino-C1xcx9cC5 alkyl groups which may have one or two C1xcx9cC3 alkyl or C7xcx9cC11 aralkyl groups as a substituent(s) on the nitrogen atom, for example, aminoethyl, aminopropyl, dimethylaminoethyl, dimethylaminopropyl, diethylaminoethyl, N-methyl-N-benzylaminoethyl, etc.; and 5- to 7-membered saturated cyclic amino-C1xcx9cC3 alkyl groups such as 1-pyrrolidinylethyl, piperidinoethyl, etc. For R8 and R9, phenyl-C1xcx9cC5 alkyl groups such as phenylethyl and the like may be exemplified as the substituted alkyl group.
The substituent of each of the lower alkylene group for Q and the vinyl or ethynyl group for Ra includes, for example, alkyl groups, substituted alkyl groups, cycloalkyl groups, cycloalkenyl groups, saturated heterocyclic groups, carboxyl group, alkoxycarbonyl groups, aromatic groups, and groups represented by the formula xe2x80x94CON(R8)R9.
As the lower alkylene group, there may be exemplified alkylene groups of 6 or less carbon atoms, such as methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, etc.
The acyl group includes, for example, formyl group; alkanoyl groups of 2 to 6 carbon atoms, such as acetyl, propanoyl, etc.; cycloalkanecarbonyl groups of 4 to 7 carbon atoms, such as cyclopropanecarbonyl, cyclobutanecarbonyl, cyclopentanecarbonyl, cyclohexanecarbonyl, etc.; cycloalkenecarbonyl groups of 3 to 6 carbon atoms, such as cyclopentenecarbonyl, cyclohexenecarbonyl, etc.; aroyl groups of 6 to 10 carbon atoms, such as benzoyl, toluoyl, naphthoyl, etc.; saturated heterocyclic ring-carbonyl groups having a 5- or 6-membered saturated heterocyclic ring containing one or two heteroatoms selected from nitrogen atom, oxygen atom and sulfur atom, for example, 2-piperidinecarbonyl, 3-morpholinecarbonyl, etc.; and heteroaromatic acyl groups having a 5- or 6-membered heteroaromatic ring containing one or two heteroatoms selected from nitrogen atom, oxygen atom and sulfur atom, for example, furoyl, thenoyl, nicotinoyl, isonicotinoyl, etc.
As the cyclic amino group which Rp and Rq form when taken together, i.e., the 5- to 7-membered saturated cyclic amino group which may contain other heteroatom(s) in the ring, there may be exemplified the same groups as those exemplified above as the cyclic amino group formed by R8 and R9.
As the group represented by the formula xe2x80x94S(O)nR7, there may be exemplified alkylsulfonyl groups of 8 or less carbon atoms, such as methylsulfonyl group, ethylsulfonyl group, propylsulfonyl group, isopropylsulfonyl group, etc.; and corresponding alkylsulfinyl groups and alkylthio groups.
As the group represented by the formula: 
there may be exemplified groups represented by the following formulas: 
Preferable example thereof are (piperidin-3-yl)oxy, (piperidin-4-yl)oxy, (1-methylpiperidin-3-yl)oxy, (1-methylpiperidin-4-yl)oxy, (pyrrolidin-3-yl)oxy, (1-methylpyrrolidin-3-yl)oxy, (piperidin-3-yl)thio, (piperidin-4-yl)thio, (1-methylpiperidin-3-yl)thio, (1-methylpiperidin-4-yl)thio, (pyrrolidin-3-yl)thio, (1-methylpyrrolidin-2-yl)thio, (piperidin-3-yl)amino, (piperidin-4-yl)amino, (1-methylpiperidin-3-yl)amino, (1-methylpiperidin-4-yl)amino, (pyrrolidin-3-yl)amino, (1-methylpyrrolidin-3-yl)amino, etc.
As the alkenyl group, there may be exemplified alkenyl groups of 6 or less carbon atoms, such as vinyl, allyl, propenyl, 2-propenyl, butenyl, pentenyl, hexenyl, etc.
As the alkynyl group, there may be exemplified alkynyl groups of 6 or less carbon atoms, such as ethynyl, propargyl, butynyl, pentynyl, etc.
As Y1, Y2, Y3 and Y4, the following may be exemplified.
1. Y1 through Y4, which may be the same or different, are independently xe2x80x94CH2xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94COxe2x80x94, xe2x80x94C(xe2x95x90C(R12)R13)xe2x80x94 or xe2x80x94N(R11)xe2x80x94.
Specific examples of Y1 through Y4 are as follows.
1-1. Y1 is xe2x80x94CH2xe2x80x94, xe2x80x94COxe2x80x94 or xe2x80x94C(xe2x95x90C(R12)R13)xe2x80x94, and Y2 through Y4, which may be the same or different, are independently xe2x80x94CH2xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94COxe2x80x94, xe2x80x94C(xe2x95x90C(R12)R13)xe2x80x94 or xe2x80x94N(R11)xe2x80x94.
1-2. Y1 is xe2x80x94CH2xe2x80x94, xe2x80x94COxe2x80x94 or xe2x80x94C(xe2x95x90C(R12)R13)xe2x80x94, Y2 and Y3 are independently xe2x80x94CH2xe2x80x94, and Y4 is xe2x80x94CH2xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94COxe2x80x94, xe2x80x94C(xe2x95x90C(R12)R13)xe2x80x94 or xe2x80x94N(R11)xe2x80x94.
1-3. Y1 is xe2x80x94CH2xe2x80x94, and Y2 through Y4, which may be the same or different, are independently xe2x80x94CH2xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94COxe2x80x94, xe2x80x94C(xe2x95x90C(R12)R13)xe2x80x94 or xe2x80x94N(R11)xe2x80x94.
1-4. Y1 is xe2x80x94CH2xe2x80x94, one of Y2 through Y4 is xe2x80x94N(R11)xe2x80x94, and the two others are independently xe2x80x94CH2xe2x80x94.
1-5. All of Y1 through Y4 are independently xe2x80x94CH2xe2x80x94.
2. One of Y1 through Y4 is a single bond, and the three others, which may be the same or different, are independently xe2x80x94CH2xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94COxe2x80x94, xe2x80x94C(xe2x95x90C(R12)R13)xe2x80x94 or xe2x80x94N(R11)xe2x80x94.
In addition, specific examples of Y1 through Y4 are as follows.
2-1. Y1 is xe2x80x94CH2xe2x80x94, xe2x80x94COxe2x80x94 or xe2x80x94C(xe2x95x90C(R12)R13)xe2x80x94, one of Y2 through Y4 is a single bond, and the two others, which may be the same or different, are independently xe2x80x94CH2xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94COxe2x80x94, xe2x80x94C(xe2x95x90C(R12)R13)xe2x80x94 or xe2x80x94N(R11)xe2x80x94.
2-2. Y1 is xe2x80x94CH2xe2x80x94, xe2x80x94COxe2x80x94 or xe2x80x94C(xe2x95x90C(R12)R13)xe2x80x94, one of Y2 and Y3 is a single bond while the other is xe2x80x94CH2xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94COxe2x80x94, xe2x80x94C(xe2x95x90C(R12)R13)xe2x80x94 or xe2x80x94N(R11)xe2x80x94, and Y4 is xe2x80x94CH2xe2x80x94.
2-3. Y1 is xe2x80x94CH2xe2x80x94, xe2x80x94COxe2x80x94 or xe2x80x94C(xe2x95x90C(R12)R13)xe2x80x94, one of Y2 and Y3 is a single bond while the other is xe2x80x94CH2xe2x80x94, and Y4 is xe2x80x94N(R11)xe2x80x94.
2-4. Y1 is xe2x80x94CH2xe2x80x94, one of Y2 and Y3 is a single bond while the other is xe2x80x94CH2xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94COxe2x80x94, xe2x80x94C(xe2x95x90C(R12)R13)xe2x80x94 or xe2x80x94N(R11)xe2x80x94, and Y4 is xe2x80x94CH2xe2x80x94.
2-5. Y1 is xe2x80x94CH2xe2x80x94, one of Y2 and Y3 is a single bond while the other is xe2x80x94CH2xe2x80x94, and Y4 is xe2x80x94N(R11)xe2x80x94.
2-6. Y1 is xe2x80x94CH2xe2x80x94, one of Y2 and Y3 is a single bond while the other is xe2x80x94N(R11)xe2x80x94, and Y4 is xe2x80x94CH2xe2x80x94.
2-7. One of Y1 through Y4 is a single bond, and the three others are independently xe2x80x94CH2xe2x80x94.
3. Two of Y1 through Y4 are independently a single bond, and the two others, which may be the same or different, are independently xe2x80x94CH2xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94COxe2x80x94, xe2x80x94C(xe2x95x90C(R12)R13)xe2x80x94 or xe2x80x94N(R11)xe2x80x94.
In addition, specific examples of Y1 through Y4 are as follows.
3-1. Y1 is xe2x80x94CH2xe2x80x94, xe2x80x94COxe2x80x94 or xe2x80x94C(xe2x95x90C(R12)R13)xe2x80x94, Y2 and Y3 are independently a single bond, and Y4 is xe2x80x94CH2xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94COxe2x80x94, xe2x80x94C(xe2x95x90C(R12)R13)xe2x80x94 or xe2x80x94N(R11)xe2x80x94.
3-2. Y1 is xe2x80x94CH2xe2x80x94, xe2x80x94COxe2x80x94 or xe2x80x94C(xe2x95x90C(R12)R13)xe2x80x94, Y2 and Y3 are independently a single bond, and Y4 is xe2x80x94CH2xe2x80x94.
3-3. Y1 is xe2x80x94CH2xe2x80x94, xe2x80x94COxe2x80x94 or xe2x80x94C(xe2x95x90C(R12)R13)xe2x80x94, Y2 and Y3 are independently a single bond, and Y4 is xe2x80x94N(R11)xe2x80x94.
3-4. Y1 is xe2x80x94CH2xe2x80x94, Y2 and Y3 are independently a single bond, and Y4 is xe2x80x94N(R11)xe2x80x94.
3-5. Two of Y1 through Y4 are independently a single bond, and the two others are independently xe2x80x94CH2xe2x80x94.
Furthermore, the present invention relates to a process for producing the compound (1), a prodrug thereof or a pharmaceutically acceptable salt of the compound (1) or prodrug. This process comprises reacting a carboxylic acid reactive derivative of the formula (2): 
wherein R1, R2, R3, R4, R5, Y1, Y2, Y3, Y4 and Z are as defined above, and J is a hydroxyl group or a leaving group replaceable by a nucleophilic reagent, with guanidine to form the guanidinocarbonyl group (xe2x80x94C(=O)N=C(NH2)2 group) shown in the formula (1), and if necessary, converting the reaction product to a pharmaceutically acceptable salt.
In the above reaction, when the acid derivative of the formula (2) has a reactive group such as hydroxyl group or amino group, the reactive group is previously protected with a suitable protective group, and the protective group is removed after carrying out the reaction, whereby a desired acylguanidine derivative (1) may be produced.
The leaving group replaceable by a nucleophilic reagent includes, for example, halogen atoms (e.g. fluorine, chlorine and bromine), lower alkoxy groups (e.g. methoxy and ethoxy), aralkyloxy groups (e.g. benzyloxy group), aryloxy groups (e.g. phenoxy group), and groups formed by a condensing agent and a compound of the formula (2) in which J is a hydroxyl group. A process for producing the carboxylic acid reactive derivative of the formula (2) in which J is any of the above-exemplified groups is concretely explained below.
As the carboxylic acid reactive derivative of the formula (2), there may be exemplified acid halides, acid anhydrides (including mixed acid anhydrides) and ester derivatives. Specific examples of the carboxylic acid reactive derivative are acid halides such as acid chlorides and acid bromides; mixed acid anhydrides of an alkyloxycarbonyl chloride type compound (e.g. ethyloxycarbonyl chloride or isobutoxycarbonyl chloride) and an xcex1-polyalkyl-substituted carboxylic acid chloride type compound (2-ethyl-n-butyryl chloride or trimethylacetyl chloride); and ester derivatives such as activated esters (e.g. p-nitrophenyl esters, N-hydroxysuccinimide esters and pentafluorophenyl esters) and common esters (e.g. methyl esters and ethyl esters). Such a carboxylic acid reactive derivative can easily be obtained from a corresponding carboxylic acid according to a conventional method.
When guanidine is reacted with the acid halide or the acid anhydride (including the mixed acid anhydride), the reaction may be carried out in a solvent in the presence of a base or excess guanidine with cooling or at room temperature. As the base, there may be exemplified inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogencarbonate, etc.; and organic bases such as triethylamine, pyridine, etc. As the solvent, there may be exemplified aromatic hydrocarbon solvents such as benzene, toluene, xylene, etc.; ether solvents such as tetrahydrofuran, 1,4-dioxane, etc.; halogenated hydrocarbon solvents such as dichloromethane, chloroform, 1,2-dichloroethane, etc.; amide solvents such as dimethylformamide, dimethylacetamide, etc.; basic solvents such as pyridine, etc.; and mixed solvents thereof.
When guanidine is reacted with the ester derivative, the reaction is carried out in a solvent in the presence of an equimolar or excess amount of guanidine with heating or cooling. When the ester derivative is an activated ester, the reaction is preferably carried out, for example, in an ether solvent (e.g. tetrahydrofuran, 1,2-dimethoxymethane or dioxane), an ester solvent (e.g. ethyl acetate), dimethylformamide, or a mixed solvent thereof. When the ester derivative is other than activated esters, the reaction is preferably carried out, for example, in an alcohol solvent (e.g. methanol, ethanol or isopropanol), an ether solvent (e.g. tetrahydrofuran, 1,2-dimethoxyethane or dioxane), dimethylformamide, or a mixed solvent thereof. After the solvent is distilled off, the residue may be heated for a short time at about 130xc2x0 C. if necessary.
The compound (1) of the present invention may be obtained by reacting a carboxylic acid of the general formula (3): 
wherein R1, R2, R3, R4, R5, Y1, Y2, Y3, Y4 and Z are as defined above, with guanidine preferably in the presence of a condensing agent in an inert solvent at room temperature or with heating.
In this reaction, when the compound of the formula (3) has a reactive group such as carboxyl group, hydroxyl group or amino group, the reactive group is previously protected with a suitable protective group, and the protective group is removed after carrying out the reaction, whereby a desired acylguanidine derivative (1) may be produced.
The reaction is preferably carried out in the presence of a condensing agent [e.g. dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIPC), 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide (WSC), benzotriazol-1-yl-tris(dimethylamino)phosphonium hexafluorophosphate (BOP), diphenylphosphonylazide (DPPA), or N,N-carbonyldiimidazole (Angew. Chem. Int. Ed. Engl., Vol. 1, 351(1962))] and optionally an additive [e.g. N-hydroxysuccinimide (HONSu), 1-hydroxy-benzotriazole (HOBt) or 3-hydroxy-4-oxo-3,4-dihydro-1,2,3-benzotriazine (HOObt)] in an aromatic hydrocarbon solvent (e.g. benzene, toluene or xylene), an ether solvent (e.g. tetrahydrofuran or 1,4-dioxane), a halogenated hydrocarbon solvent (e.g. dichloromethane, chloroform or 1,2-dichloroethane), an amide solvent (e.g. dimethylformamide or dimethylacetamide), a basic solvent (e.g. pyridine), or a mixed solvent thereof.
In the above-mentioned production, as the protective group for the reactive group such as hydroxyl group, amino group or carboxyl group, protective groups conventionally used in the field of organic synthetic chemistry may be used. The introduction and removal of such a protective group may be carried out by a conventional method (for example, Protective Groups in Organic Synthesis, JOHN WILLEY and SONS, 1991).
The protective group for the hydroxyl group includes, for example, methoxymethyl group and tetrahydropyranyl group. The protective group for the amino group includes, for example, tert-butoxycarbonyl group. Such a protective group for the hydroxyl group may be removed by reaction in a solvent such as aqueous methanol, aqueous ethanol or aqueous tetrahydrofuran in the presence of an acid such as hydrochloric acid, sulfuric acid or acetic acid. The protective group for the amino group may be removed by reaction in a solvent such as aqueous tetrahydrofuran, methylene chloride, chloroform or aqueous methanol in the presence of an acid such as hydrochloric acid or trifluoroacetic acid.
As a form in which the carboxyl group is protected, there may be exemplified tert-butyl esters, orthoesters and acid amides. The protective group used for this protection is removed as follows. In the case of the tert-butyl esters, the removal is carried out, for example, by reaction in an aqueous solvent in the presence of hydrochloric acid. In the case of the orthoesters, the removal is carried out by treatment with an acid and then an alkali such as sodium hydroxide in a solvent such as aqueous methanol, aqueous tetrahydrofuran or aqueous 1,2-dimethoxyethane. In the case of the acid amides, the removal may be carried out by reaction in a solvent such as water, aqueous methanol or aqueous tetrahydrofuran in the presence of an acid such as hydrochloric acid or sulfuric acid.
The compounds of the general formula (2) and the general formula (3), i.e., the starting compounds in the above-mentioned production processes, respectively, are known in literature or may be produced from compounds known in literature according to processes known in literature [for example, Bull. Soc. Chim. Fr., 2(1982), 3-4, 116-124; J. Org. Chem., 48(1983) 26, 5327-5332; J. Chem. Soc., 108(1986) 7, 1617-1632; J. Chem. Soc., Perkin Trans. 1, 4(1993), 405-410; J. Org. Chem., 53(1988) 20, 4716-4719; J. Am. Chem. Soc., 105(1983) 6, 1586-1590; Synthesis, 2(1985), 169-171; and Synthetic Communications, 18(1998) 4, 343-349]. The carboxylic acid of the general formula (3) can easily be derived from a corresponding ester of the general formula (2) in which J=OR wherein R is a lower alkyl group such as methyl or ethyl, by a conventional hydrolysis reaction. The carboxylic acid reactive derivative of the general formula (2) may be synthesized from the carboxylic acid of the general formula (3) according to a conventional process.
There is given below examples of process for synthesizing each of esters of the general formulas (1d) and (1f) which correspond the general formula (2) in which J=OR wherein R is an alkyl group such as methyl or ethyl.
The esters of the general formulas (1d) and (1f) may be synthesized according to the following reaction formulas: 
wherein R1, R2, R3, R4, R5, Y1, Y2, Y3, Y4 and Z are as defined above, and R and Rxe2x80x2, which may be the same or different, are independently a lower alkyl group.
The step (a) may be carried out by reacting a compound (1a) with a carbonic acid ester (e.g. diethyl carbonate or dimethyl carbonate), a phosphonoformic acid ester (e.g. ethyl diethylphosphonoformate), an oxalic acid ester (e.g. diethyl oxalate or dimethyl oxalate) or the like usually at 20xc2x0 C. to 100xc2x0 C. in the presence of a base (e.g. sodium hydride, sodium ethoxide or sodium methoxide) in an inert solvent (e.g. benzene, toluene, diethyl ether, tetrahydrofuran, dioxane, ethanol or N,N-dimethylformamide).
The reduction of a ketone in the step (b) may be carried out by the use of sodium tetrahydroborate, for example, in an alcohol (e.g. methanol or ethanol) usually at xe2x88x9230xc2x0 C. to 30xc2x0 C.
The dehydrating reaction in the step (c) may be carried out, for example, by treating a compound (1c) with a solvent (e.g. water) containing a suitable acid (e.g. sulfuric acid, acetic acid, hydrochloric acid, boric acid, oxalic acid or p-toluenesulfonic acid) usually at 20xc2x0 C. to 100xc2x0 C. Alternatively, the following reaction conditions may be employed. That is, the dehydrating reaction may be carried out also by reacting a compound (1c) with a halogenating agent (e.g. thionyl chloride) or a sulfonating agent (e.g. methanesulfonyl chloride or p-toluenesulfonyl chloride) usually at xe2x88x9220xc2x0 C. to 30xc2x0 C. either in an inert solvent (e.g. chloroform, methylene chloride, tetrahydrofuran or N,N-dimethylformamide) in the presence of a base (e.g. triethylamine), or in a basic solvent (e.g. pyridine).
The step (d) may be carried out, for example, by reacting a compound (1b) with a diazoalkane (e.g. diazomethane) usually at xe2x88x9220xc2x0 C. to 30xc2x0 C. Alternatively, the following reaction conditions may be employed. That is, the step (d) may be carried out also by reacting a compound (1b) with an alkyl halide or a sulfonic ester [e.g. an alkyl p-toluenesulfonate (e.g. methyl p-toluenesulfonate) or a dialkyl sulfate (e.g. dimethyl sulfate)] usually at xe2x88x9220xc2x0 C. to 30xc2x0 C. in an inert solvent (e.g. N,N-dimethylformamide or N-methyl-2-pyrrolidinone) in the presence of a base (e.g. potassium hydride, sodium hydride, potassium 1,1,1,3,3,3-hexamethyldisilazide, potassium tert-butoxide or potassium carbonate).
The step (e) can be carried out, for example, by reacting a compound (1e) with a Grignard reagent (R1MgX wherein X is a halogen atom such as iodine, bromine or chlorine) usually at xe2x88x9230xc2x0 C. to 30xc2x0 C. in an inert solvent (e.g. diethyl ether or tetrahydrofuran).
In each of the above-mentioned synthesis processes, when the intermediate compound used in any of the steps has a reactive group such as carboxyl group, hydroxyl group or amino group, the reactive group is previously protected with a suitable protective group, and the protective group is removed if necessary after carrying out the step, whereby a desired compound of the general formula (2) or (3) may be produced.
As the compound of the general formula (1) produced in the manner described above, the following compounds may be exemplified.
The compound of the general formula (1) of the present invention has the acylguanidine moiety shown in the above formula (1) and has tautomers. In detail, there are a tautomer [xe2x80x94C(O)Nxe2x95x90C(NH2)2] whose acylguanidine moiety is diaminomethyleneamino, and another tautomer [xe2x80x94C(O)NHxe2x80x94C(xe2x95x90NH)NH2] whose acylguanidine moiety is aminoiminomethylamino. These tautomers are different only in state and are the same compound. Therefore, the present invention includes both of the tautomers.
The compound of the general formula (1) includes those having an optical center of asymmetry. The compound having an optical center of asymmetry may be obtained as a racemic modification, or it may be obtained as an optically active substance when an optically active starting material is used. If necessary, the racemic modification obtained may be physically or chemically resolved into optical antipodes by a conventional method. Preferably, diastereomers are formed from the racemic mixture by a reaction using a reagent for optical resolution. The diastereomers different in form may be resolved by a conventional method such as fractional crystallization.
As the xe2x80x9cprodrugxe2x80x9d, there may be exemplified those which are easily hydrolyzed in a living body to regenerate the compound of the formula (1). For example, when the compound of the formula (1) has a carboxyl group, examples of the prodrug are compounds obtained by converting the carboxyl group to an alkoxycarbonyl group, an alkylthiocarbonyl group or an alkylaminocarbonyl group. For example, when the compound of the formula (1) has an amino group, examples of the prodrug are compounds obtained by converting the amino group to an alkanoylamino group by substitution by the alkanoyl group, compounds obtained by converting the amino group to an alkoxycarbonylamino group by substitution by the alkoxycarbonyl group, and compounds obtained by converting the amino group to an acyloxymethylamino group or hydroxylamine. For example, when the compound of the formula (1) has a hydroxyl group, examples of the prodrug are compounds obtained by converting the hydroxyl group to an acyloxy group by substitution by the above-exemplified acyl group, and compounds obtained by converting the hydroxyl group to a phosphoric ester or an acyloxymethyloxy group. Examples of the alkyl portion of the group used for such conversion to the prodrug are the above-exemplified alkyl groups. The alkyl groups may be substituted by, for example, an alkoxy group of 1 to 6 carbon atoms. Preferable examples of the alkyl portion are as follows. For example, in the case of compounds obtained by converting the carboxyl group to an alkoxycarbonyl group, the alkoxycarbonyl group includes lower (number of carbon atoms: for example, 1 to 6) alkoxycarbonyl groups such as methoxycarbonyl, ethoxycarbonyl, etc.; and lower (number of carbon atoms: for example, 1 to 6) alkoxycarbonyl groups substituted by an alkoxy group, such as methoxymethoxycarbonyl, ethoxymethoxycarbonyl, 2-methoxyethoxycarbonyl, 2-methoxyethoxymethoxycarbonyl, pivaloyloxymethoxycarbonyl, etc.
If necessary, the compound of the general formula (1) or the prodrug thereof may be converted to a pharmaceutically acceptable addition salt with an inorganic acid or an organic acid. As such an acid addition salt, there may be exemplified salts with mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, etc.; salts with organic carboxylic acids such as formic acid, acetic acid, fumaric acid, maleic acid, oxalic acid, citric acid, malic acid, tartaric acid, aspartic acid, glutamic acid, etc.; and salts with sulfonic acids such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, hydroxybenzenesulfonic acid, dihydroxybenzenesulfonic acid, etc.
If necessary, the compound of the general formula (1) or the prodrug thereof may be converted to a pharmaceutically acceptable base addition salt in some cases. As such a base addition salt, there may be exemplified ammonium salt, lithium salt, sodium salt, potassium salt, calcium salt and magnesium salt.
Each of the compounds of the general formula (1), the prodrugs thereof and the pharmaceutically acceptable salts of the compounds or prodrug may be in the form of an anhydride, hydrate or solvate.
The compounds of the general formula (1), the prodrugs thereof or the pharmaceutically acceptable salts of the compounds or prodrugs inhibit the sodium/proton (Na+/H+) exchange transport system and hence are useful as a therapeutic or prophylactic agent for diseases caused by a trouble with the sodium/proton (Na+/H+) exchange transport system, for example, hypertension, organ disorders associated with ischemia or ischemic reperfusion, arrhythmia, angina pectoris, diabetes mellitus, cardiac hypertrophy, cerebro-ischemic disorders, diseases caused by excessive cell proliferations, or diseases caused by endotherial cell injury.
When used as a pharmaceutical composition, the compound of the present invention, the prodrug thereof or the pharmaceutically acceptable salt of the compound or prodrug may be orally or parenterally administered. That is, the compound, prodrug or salt may be orally administered in a usual dosage form such as powder, granules, tablets, capsules, syrup, suspension or the like, or the compound, prodrug or salt may be parenterally administered, for example, by injection of a solution, emulsion or suspension prepared from the compound, prodrug or salt. The compound, prodrug or salt may be administered rectally in the form of a suppository. The compound, prodrug or salt may be formulated into the above-exemplified suitable dosage form by blending the compound, prodrug or salt as an active ingredient with conventional acceptable adjuvants such as a carrier, excipient, binder, stabilizer and diluent. When the compound, prodrug or salt is used in the form of an injection, the injection may contain acceptable additives such as a buffer, solubilizer and tonicity agent. Although the dose and the number of administrations are varied depending on, for example, a disease to be cured, the condition of the disease, age, body weight and administration route, the compound, prodrug or salt may be administered to an adult in a dose of usually 0.1 to 2,000 mg, preferably 1 to 200 mg per day in one portion or several portions.